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Molecular BiologyUniversity of Colorado

Our group has two major research interests: 1) investigate
the biochemical mechanisms by which proteasomal activities are regulated in
cells; and 2) determine new functions of the spinal muscular atrophy protein –
survival motor neuron.We use biochemical, cell biological and
proteomics approaches for our studies.

Regulating proteasomal activitiesThe 26S proteasome is an approximately 3 Mega
Dalton large protease that is responsible for degradation of the majority of
intracellular proteins in eukaryotic cells. Usually, protein substrates of the
26S proteasome are modified with a polyubiquitin chain through a cascade of
enzymatic reactions requiring a ubiquitin activating enzyme (E1), a ubiquitin
conjugating enzyme (E2) and a ubiquitin ligase (E3). In human cells there are
more than one thousand enzymes that are involved in mediating protein
ubiquitination and deubiquitination. The 26S proteasome is consisted of 33
different proteins that catalyze multiple activities. 1) Binding of
polyubiquitin chains by which the proteasome recruits substrates. 2) Deubiquitinating
substrates by which ubiquitin is recycled. 3) Hydrolysis of ATP that promotes unfolding
and translocation of substrates for degradation. 4) Hydrolysis of polypeptides
by which substrate proteins are degraded. The biochemistry of
proteasome-mediated protein degradation is fascinating, which requires
coordinated actions of all proteasomal activities. Moreover, proteasomal
degradation is highly regulated by factors that control proteasome assembly
and/or proteasomal activities. Currently, we are investigating how human 26S proteasome-associating
proteins regulate proteasomal activities. Mechanistically,
proteasome-associating proteins may regulate processing of substrates, modification
of proteasomal subunits or conformation, which in turn could

regulate proteasomal
degradation.

Determining new functions of survival motor neuronSpinal muscular atrophy (SMA) is the leading genetic
disorder for causing infant death with an incidence of 1/10,000 in living births.SMA is caused by low levels of survival motor
neuron (SMN) protein, it is unknown why low protein levels of SMN cause a specific
motor neuron disease. Studies using mice have suggested that increase of SMN protein
levels can ameliorate the disease symptom and significantly extend the life
span of SMA mice. Thus, means that increase SMN protein levels are potential
therapies for SMA. One of our goals is to identify modulators that play critical
roles in mediating SMN protein levels at the posttranscriptional level. For
instance, we are identifying ubiquitin ligases and deubiquitinating enzymes
that mediate proteasomal degradation of SMN. Therapeutically, we expect that
some of the SMN protein stability modulators are potential drug targets of SMA.
The other goal is to explore new functions of SMN, especially its roles in
mediating neuron growth and signaling events.Understanding of SMN functions may help us to uncover the pathogenesis
of SMA.

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